Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis

Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus

Specific Aim 1: To investigate whether, in Lymphangioleiomyomatosis (LAM) patients, the combination of sirolimus and hydroxychloroquine is safe and well tolerated

Specific Aim 2: To investigate whether, in LAM patients, 6 months of combination therapy with sirolimus and hydroxychloroquine results in improvement of indicators of disease, and whether the gains are sustained after stopping therapy.

Specific Aim 3: To investigate the potential role of a LAM-specific peripheral blood signature to predict rates of disease progression and determine responsiveness to combination therapy.

This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken orally daily. Up to 18 adult women with LAM will be enrolled.

This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken orally daily for 6 months. The study is to be conducted at 2 sites. Up to 18 adult women with LAM will be enrolled, and each recruiting site will recruit between 8-12 subjects. The protocol will use the following eligibility criteria.

Inclusion Criteria:

• Female age 18 or older

• Ability to give informed consent

• Diagnosis of LAM as defined as typical cystic change on CT plus:

  • biopsy or cytology of any tissue demonstrating LAM
  • angiomyolipoma, chylothorax, lymphangioleiomyoma, or tuberous sclerosis
  • serum VEGFD greater or equal to 800pg/ml

• Post-bronchodilator FEV1 equal or less than 80% of predicted or DLCO equal equal or less than 70% of predicted, or RV > 120% of predicted at baseline

• Women of childbearing potential must agree to use 2 forms of barrier contraception during and for 8 weeks after the last dose of medication.

Exclusion Criteria:

• History of intolerance of mTOR inhibitors
• History of intolerance to hydroxychloroquine
• History of severe psoriasis
• History of porphyria cutanea tarda
• Uncontrolled intercurrent illness
• Pregnant, breast feeding, or plan to become pregnant in the next year
• Inadequate contraception
• Significant hematological or hepatic abnormalities
• Use of an investigational drug within 30 days of study start
• Inability to attend scheduled clinic visits
• Inability to perform PFTs
• Creatinine > 2.5mg/dL
• Recent pneumothorax within 8 weeks of screening
• History of malignancy in the last 2 years other than basal cell skin cancer
• Use of estrogen containing medication within 30 days of screening
• Abnormal G6PD levels at baseline
• Preexisting maculopathy or retinopathy
• Preexisting myopathy
• Currently taking doxycycline, metformin, lupron, simvastatin
• Unable to undergo CT or MRI
• History of seizure within last year
• Hepatitis B, C, HIV positive serology
• Use of alternative medical therapies for LAM for at least 6 weeks prior to study participation
• History of myocardial infarct, angina, or stroke related to atherosclerosis
• History of cardiomyopathy
• Previous lung transplant
• Surgery (involving entry into a body cavity or requiring 3 or more stitches) within 2 months of initiation of study drug
• Uncontrolled cholesterol > 350mg/dL, triglycerides > 400mg/dL